The cystatins belong to a large superfamily of proteins, many of which inhibit cysteine proteases of the C1 class (cathepsins). Virtually all organisms produce one or more members of the cystatin superfamily, often multiple types. Basically, there are three major cystatin families, the types I, II, and III cystatins and a number of cystatin-related protein families (1). While new physiological processes are being tied to the cystatins, it is their links to several human pathologies which command the most attention. The use of Cystatin C as a marker of kidney function in various disease states is very well studied (2). Cystatin has also been linked to both cancer and Alzheimer's disease (3,4). While the cystatin link to Alzheimer's is still being worked out, a number of important studies have proposed cystatins as potent inhibitors of various cancers.
Metastasis or the spread and growth of cancer is the primary reason for cancer treatment failure and loss of life from cancer. Metastasis is very difficult to treat because metastatic cancers are usually resistant to cancer therapies and metastatic cancers spread systemically and relentlessly in the cancer patient, outstripping any treatment strategy. Currently, there are no purely anti-metastatic agents in clinical use. We first found that Cystatin C, a natural cysteine protease inhibitor, exhibits anti-metastatic effects on melanoma, one of the most metastatic of all cancers (5). We found that Cystatin C genetic overexpression inhibits melanoma cell migration and invasion (6). Another study by our laboratory showed Cystatin C overexpression inhibits metastasis by inducing higher levels of melanoma cell death in lungs of animals after melanoma cell injection (7). Work by other groups showed that Cystatin C is also anti-metastatic for a number of other cancers (glioblastoma, breast, prostate, and colorectal (cystatin D) when overexpressed (8,9,10,11). We believe that critical anti-metastatic effects derived from cystatin must be able to account for increased apoptosis of metastatic cancer cells and/or cancer cell migration inhibition. Of course intact cystatin, as a cysteine protease inhibitor, may also function as an inhibitor of cathepsin-type proteases and hence may partially inhibit invasion for some cancers. We do not believe, however, the protease inhibitory activity of cystatin is critical to cystatin's anti-metastatic action because of the partial inhibition of cancer cell metastasis shown by synthetic cysteine protease inhibitors (12).
Needed in the art an the improved method of treating metastatic cancer with Cystatin C.